The overall objective of this project is to elucidate certain immunologic and genetic mechanisms which disrupt the formation or maintenance of the myelin membrane. The five projects and core described in this program utilize experimental animal models and in vitro systems to study these mechanisms and evaluate their relevance to human demyelinating diseases such as multiple sclerosis. Three projects make use of EAE as a model for studying immune responses which damage or protect CNS myelin. One of these projects will pursue specific studies of the cellular mechanisms involved in "spontaneous" suppression of the disease. Another will also stress investigation of the means by which the disease may be suppressed as well as studies on the possible immune viral etiology of the human disease. In the third project these approaches merge in an extended examination of neurotoxin derivatives and peptides which clearly induce an unresponsive immune state and extend the range of peptide structures which may be considered for effective immuno-suppression. The remaining two projects examine mechanisms of disruption of myelin formation at the cellular and molecular levels. One of these studies will examine genetic regulation of myelination through detailed morphometric and biochemical analysis of the abnormal proliferation and differentiation of oligodendroglia found in CNS of the mosaic female carriers of the jimpy gene. Understanding the mechanisms by which recovery of the myelin deficit occurs in part of the brain promises to increase understanding of factors which lead to remyelination during recovery from pathologic conditions. The remaining project utilizes brain slices in vitro to examine the direct effects of specific antibodies to myelin components on assembly of the myelin membrane. Determination of the sequence of biochemical and morphologic events leading to disruption of myelin assembly by antibodies will increase our knowledge of fundamental interactions between the nervous and immune systems.